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FI3365334T3 - Bentsolaktaamiyhdisteitä proteiinikinaasin estäjinä - Google Patents

Bentsolaktaamiyhdisteitä proteiinikinaasin estäjinä Download PDF

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FI3365334T3
FI3365334T3 FIEP16788794.2T FI16788794T FI3365334T3 FI 3365334 T3 FI3365334 T3 FI 3365334T3 FI 16788794 T FI16788794 T FI 16788794T FI 3365334 T3 FI3365334 T3 FI 3365334T3
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yyl
chloro
dihydro
oxo
isoindol
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FIEP16788794.2T
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Swedish (sv)
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Valerio Berdini
Ildiko Maria Buck
James Edward Harvey Day
Charlotte Mary Griffiths-Jones
Thomas Daniel Heightman
Steven Howard
Christopher William Murray
David Norton
Marc O'reilly
Alison Jo-Anne Woolford
Michael Liam Cooke
David Cousin
Stuart Thomas Onions
Jonathan Martin Shannon
John Paul Watts
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Otsuka Pharma Co Ltd
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Priority claimed from GBGB1518676.0A external-priority patent/GB201518676D0/en
Priority claimed from GBGB1611351.6A external-priority patent/GB201611351D0/en
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Publication of FI3365334T3 publication Critical patent/FI3365334T3/fi

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Claims (9)

Patenttivaatimukset
1. Yhdiste, jolla on kaava (2): RY — pa Nin 0 xy p N J g N TNT H (2) tai sen farmaseuttisesti hyväksyttävä suola tai tautomeeri; jossa n on 1 tai 2; Z on valittu C-RZ:sta ja N:stä; R? on valittu vedystä; halogeenista; metoksista ja C1-3-alkyylistä, joka on valinnaisesti substituoitu hydroksilla tai metoksilla; R! on valittu seuraavista: - -(Alk'-Cyc'; jossa t on Otai 1 ja Alk! on suora- tai haaraketjuinen C1-4-alkyleeniryhmä, joka on valinnaisesti substituoitu 1 tai 2 hydroksiryhmällä; ja — - asykliset C1-6-hiilivetyryhmät, jotka ovat substituoimattomia tai substituoituja 1, 2 tai 3 substituentilla R*, jotka on valittu hydroksista; oksosta; fluorista ja syaanista; ja jolloin 1 tai 2 mutta eivät kaikki hiilivetyryhmän hiiliatomeista voi olla korvattu O:lla tai N:llä; Cyc! on syklinen ryhmä, joka on valittu (a) 3-9-jäsenisistä ei-aromaattisista monosyklisistä ja bisyklisistä karbosyklisistä ja heterosyklisistä ryhmistä, jotka — sisältävät 0, 1, 2 tai 3 renkaan heteroatomijäsentä, jotka on valittu O:n, N:n, S:n, S(O):n ja S(O)z:n joukosta; (b) 5—6-jäsenisistä monosyklisistä heteroaryyliryhmistä, jotka sisältävät 1, 2 tai 3 renkaan heteroatomijäsentä, joista 1 on N ja muut, mikäli niitä on, on valittu O:n, N:n ja S:n joukosta; ja (c) 3—7-jasenisistd monosyklisistä karbosyklisistä ryhmistä; jolloin kukin syklinen ryhmä (a), (b) ja (c) on substituoimaton tai substituoitu 1,2 tai 3 substituentilla R$, joka on valittu ryhmistä hydroksi; okso; fluori; amino; NH(Hyd"); N(Hyd")2; O-Hyd!; -C(=O)-Hyd!: -C(=0)-0-Hyd! ja Hyd"; jolloin Hyd" on ei- aromaattinen C1-4-hiilivetyryhmä, joka on valinnaisesti substituoitu yhdellä tai useammalla fluorista, hydroksiylistä ja metoksista valitulla substituentilla;
R? on valittu vedystä; halogeenista ja Cr hiilivetyryhmistä, jotka on valinnaisesti substituoitu yhdellä tai useammalla fluoriatomilla;
R3 on vety tai ryhmä L!-R?:
R on valittu vedystä; metoksista ja C1-3-alkyylistä, joka on valinnaisesti substituoitu — hydroksilla, aminolla, mono- tai di-C1-2-alkyyliaminolla, syklisellä aminoryhmällä tai metoksilla; jolloin syklinen aminoryhmä on tyydyttynyt 4-7-jäseninen heterosyklinen ryhmä, joka sisältää renkaan typpijäsenen ja valinnaisesti toisen O:sta, N:stä ja S:stä valittavan renkaan heteroatomijäsenen, jolloin syklinen aminoryhmä on liittynyt sen renkaan typpijäsenen kautta Ci-s-alkyylin ja jolloin syklinen aminoryhmä on
— valinnaisesti substituoitu yhdellä tai kahdella metyyliryhmällä; edellyttäen, että enintään yksi R* voi olla muu kuin vety tai metyyli;
[' on valittu sidoksesta; Alk?:sta, Alk?-O:sta ja Alk?-C(=O):sta, jolloin Alk? on suoraketjuinen tai haarautunut C1-4-alkyleeniryhmä, joka on valinnaisesti substituoitu yhdellä tai useammalla substituentilla, jotka on valittu hydroksista, metoksista,
— aminosta, metyyliaminosta, dimetyyliaminosta ja fluorista;
R” on valittu seuraavista: e vety
+ CO2H
+ NR?R?
— » karbosyklinen tai heterosyklinen ryhmä, jossa on 3—12 rengasjäsentä, joista O, 1, 2 tai 3 on renkaan heteroatomijäseniä, jotka on valittu O:n, N:n ja S:n ja S:n hapettuneiden muotojen joukosta, jolloin karbosyklinen tai heterosyklinen ryhmä on valinnaisesti substituoitu yhdellä tai useammalla substituentilla R!9; ja + asyklinen C1--hiilivetyryhmä, joka on valinnaisesti substituoitu yhdellä tai useammalla substituentilla, jotka on valittu hydroksista; oksosta; halogeenista; syaanista; karboksista; aminosta; mono- tai di-C1-4-alkyyliaminosta ja karbosyklisistä ja heterosyklisistä ryhmistä, joissa on 3—12 rengasjäsentä, joista 0, 1, 2 tai 3 on renkaan heteroatomijäseniä, jotka on valittu O:n, N:n ja S:n ja S:n hapettuneiden muotojen joukosta, jolloin karbosyklinen tai heterosyklinen ryhmä on valinnaisesti
— substituoitu yhdellä tai useammalla substituentilla R!9; jolloin yksi tai kaksi mutta eivät kaikki asyklisen C1-s-hiilivetyryhmän hiiliatomeista voi olla valinnaisesti korvattu O:lla, S:llä, SO:lla, SOz:lla tai NR'':llä;
R& on valittu vedystä ja C414-hiilivetyryhmästä, jolloin C14-hiilivetyryhmä on valinnaisesti substituoitu 1-2 substituentilla, jotka on valittu hydroksista, aminosta,
mono-C1-4-alkyyliaminosta, di-C1.s-alkyyliaminosta ja 4—7-jäsenisistä tyydyttyneistä heterosyklisistä renkaista, jotka sisältävät 1-2 renkaan heteroatomijäsentä, jotka on valittu O:n ja N:n joukosta, jolloin mono-C1-4-alkyyliamino-, di-C1-4-alkyyliamino- ja 4— 7-jäseniset tyydyttyneet heterosykliset renkaat on kukin valinnaisesti substituoitu 1:llä— —2:lla hydroksi- tai C1-3-alkyylisubstituentilla; R? on valittu seuraavista: e vety + karbosyklinen tai heterosyklinen ryhmä, jossa on 3—12 rengasjäsentä, joista O, 1, 2 tai 3 on renkaan heteroatomijäseniä, jotka on valittu O:n, N:n ja S:n ja S:n — hapettuneiden muotojen joukosta, jolloin karbosyklinen tai heterosyklinen ryhmä on valinnaisesti substituoitu yhdellä tai useammalla substituentilla R!9; ja + asyklinen C1--hiilivetyryhmä, joka on valinnaisesti substituoitu yhdellä tai useammalla substituentilla, jotka on valittu hydroksista; oksosta; halogeenista; syaanista; karboksista; aminosta; mono- tai di-C1-4-alkyyliaminosta ja karbosyklisistä ja heterosyklisistä ryhmistä, joissa on 3-12 rengasjäsentä, joista 0, 1, 2 tai 3 on renkaan heteroatomijäseniä, jotka on valittu O:n, N:n ja S:n ja S:n hapettuneiden muotojen joukosta, jolloin karbosyklinen tai heterosyklinen ryhmä on valinnaisesti substituoitu yhdellä tai useammalla substituentilla R'9; jolloin yksi tai kaksi mutta eivät kaikki asyklisen C1-s-hiilivetyryhmän hiiliatomeista voi olla valinnaisesti korvattu O:lla, — S:llä, SO:lla, SOz:lla tai NR?':llä; tai NR8R® muodostaa heterosyklisen ryhmän, jossa on 4-12 rengasjäsentä, jolloin NR8R%:n typpiatomin lisäksi heterosyklinen ryhmä sisältää valinnaisesti 1 tai 2 muuta renkaan heteroatomijäsentä, jotka on valittu O:n, N:n ja S:n ja S:n hapettuneiden muotojen joukosta; ja jolloin heterosyklinen ryhmä on valinnaisesti substituoitu yhdellä tai useammalla substituentilla R'?; R'0 on valittu seuraavista: + halogeeni; hydroksi; okso; syaani « OR"? jossa R'? on C1-6-alkyyli tai C3-6-sykloalkyyli, joista kukin on valinnaisesti substituoitu halogeenilla + asyklinen C41--hiilivetyryhmä, joka on valinnaisesti substituoitu yhdellä tai useammalla substituentilla, jotka on valittu hydroksista; oksosta; halogeenista; syaanista; karboksista; aminosta; mono- tai di-C1-4-alkyyliaminosta ja karbosyklisistä ja heterosyklisistä ryhmistä, joissa on 3—7 rengasjäsentä, joista 0, 1, 2, 3 tai 4 on renkaan heteroatomijäseniä, jotka on valittu N:n, O:n ja S:n joukosta, jolloin karbosykliset tai heterosykliset ryhmat on valinnaisesti substituoitu yhdellä tai useammalla substituentilla R'3, jotka on valittu hydroksista; halogeenista; syaanista; aminosta; -NH(Hyd'):stä; -N(Hyd")2:sta ja -(O)v-Hyd!:stä, jolloin v on O tai 1; jolloin yksi tai kaksi mutta eivät kaikki asyklisen C1-e-hiilivetyryhmän hiiliatomeista voi olla — valinnaisesti korvattu O:lla, S:llä, SO:lla, SOz:lla tai NR'':llä; ja + karbosykliset tai heterosykliset ryhmät, joissa on 3—7 rengasjäsentä, joista 0, 1, 2, 3 tai 4 on renkaan heteroatomijäseniä, jotka on valittu N:n, O:n ja S:n joukosta, jolloin karbosykliset tai heterosykliset ryhmät on valinnaisesti substituoitu yhdellä tai useammalla substituentilla R'3; ja RY on valittu vedystä ja C1-4-hiilivetyryhmästä.
2. Patenttivaatimuksen 1 mukainen yhdiste, jolla on yleiskaava (3): R pa N o 7 A RS | SN PR H (3) tai sen farmaseuttisesti hyväksyttävä suola tai tautomeeri; jossa R', R?, R3, R? ja Z ovat patenttivaatimuksen 1 mukaisia; ja
3. Patenttivaatimuksen 1 mukainen yhdiste, jolla on yleiskaava (5): R? Rt N 0 7 PZ Ci ; S , ” N (5) tai sen farmaseuttisesti hyväksyttävä suola tai tautomeeri; jossa R', R?, R? ja Z ovat — patenttivaatimuksen 1 mukaisia.
4. Patenttivaatimuksen 1 mukainen yhdiste, jolla on yleiskaava (6):
eo AK Rå N O Ny PP Ro 1 NNR H (6) tai sen farmaseuttisesti hyväksyttävä suola tai tautomeeri, jossa R'!, R+, R7, Alk? ja Z ovat patenttivaatimuksen 1 mukaisia; tai
5 5. Patenttivaatimuksen 1 mukainen yhdiste, jolla on yleiskaava (7): ee Åk? Ra N o Ny p Cl | NN a AI H (R (7) tai sen farmaseuttisesti hyväksyttävä suola tai tautomeeri, jossa R+, R$, R7, Alk? ja Z ovat patenttivaatimuksen 1 mukaisia ja v on O, 1, 2 tai 3; tai
6. Patenttivaatimuksen 1 mukainen yhdiste, jolla on yleiskaava (8): RE i et ÅK pa N 0 Iz p TA 1 NÖWE H (8)
tai sen farmaseuttisesti hyväksyttävä suola tai tautomeeri; jossa R! R* R3, RY, Alk? ja Z ovat patenttivaatimuksen 1 mukaisia.
7. Patenttivaatimuksen 1 mukainen yhdiste, jolla on kaava (9): Re ol Aik? Rå N € Cl | SN (3 NÅN A 6 5 H G tai sen farmaseuttisesti hyväksyttävä suola tai tautomeeri, jossa R+, R$, R8, R9, Alk?, Z ovat patenttivaatimuksen 1 mukaisia ja v on O, 1, 2 tai 3.
8. Patenttivaatimuksen 7 mukainen yhdiste tai sen farmaseuttisesti hyväksyttävä suola tai tautomeeri, jossa R? on vety; von O; R3 on vety; R® on asyklinen tyydyttynyt C1-3-hiilivetyryhmä, joka on valinnaisesti substituoitu — yhdellä tai useammalla (esim. kahdella) substituentilla, jotka on valittu hydroksi- ja fenyyliryhmästä, jolloin fenyyliryhmä on valinnaisesti substituoitu yhdellä tai useammalla (esim. yhdellä tai kahdella) substituentilla R!9; R10 on valittu fluorista, metyylistä, metoksista ja dimetyyliaminosta; Alk? on valittu CH2:sta ja CH(CH3):sta; ja ZonCH.
9. Yhdiste, joka on valittu seuraavista: 2-(6-15-kloori-2-[(oksan-4-yylijamino]pyrimidin-4-yyli]-1-okso-2,3-dihydro-1H-isoindol- 2-yylijetikkahappo N-tert-butyyli-2-(6-{5-kloori-2-[(oksan-4-yyli)Jamino]pyrimidin-4-yyli}-1-okso-2,3- dihydro-1H-isoindol-2-yyli)-N-metyyliasetamidi
2-(6-(5-kloori-2-[(oksan-4-yylijamino]pyrimidin-4-yylij-1 -okso-2,3-dihydro-1H-isoindol- 2-yyli)-N-(1-metyylisyklobutyyli)asetamidi 2-(6-15-kloori-2-[(oksan-4-yylijamino]pyrimidin-4-yyli]-1-okso-2,3-dihydro-1H-isoindol- 2-yyli)-N-(1-metyylisykloheksyyli)asetamidi
—6-15-kloori-2-[(oksan-4-yylijamino]lpyrimidin-4-yyli)-2-[2-(2-metyylipyrrolidin-1-yyli)-2- oksoetyyli]-2,3-dihydro-1H-isoindol-1-oni 6-{5-kloori-2-[(oksan-4-yyliyamino]pyrimidin-4-yyli}-2-[2-okso-2-(3-fenyylipyrrolidin-1- yyli)etyyli]-2,3-dihydro-1H-isoindol-1-oni 2-(6-15-kloori-2-[(oksan-4-yylijamino]pyrimidin-4-yyli]-1-okso-2,3-dihydro-1H-isoindol-
2-yyli)-N-(3-metyylioksetan-3-yyli)asetamidi 2-(6-15-kloori-2-[(oksan-4-yylijamino]pyrimidin-4-yyli]-1-okso-2,3-dihydro-1H-isoindol- 2-yyli)-N-(4,4-difluorisykloheksyylijasetamidi 6-{5-kloori-2-[(oksan-4-yyliyamino]pyrimidin-4-yyli}-2-[2-(2,3-dihydro-1H-isoindol-2- yyli)-2-oksoetyyli]-2,3-dihydro-1H-isoindol-1-oni
6-{5-kloori-2-[(oksan-4-yyli)amino]pyrimidin-4-yyli}-2-[2-(4,4-difluoripiperidin-1-yyli)-2- oksoetyyli]-2,3-dihydro-1H-isoindol-1-oni 2-(6-{5-kloori-2-[(oksan-4-yyli)amino]pyrimidin-4-yyli}-1-okso-2,3-dihydro-1H-isoindol- 2-yyli)-N-(1,1,1-trifluori-2-metyylipropan-2-yylijasetamidi 6-{5-kloori-2-[(oksan-4-yyliyamino]pyrimidin-4-yyli}-2-[2-0ks0-2-(5,6,7,8-tetrahydro-
1,7-naftyridin-7-yyli)etyyli]-2,3-dihydro-1H-isoindol-1-oni 6-{5-kloori-2-[(oksan-4-yyliyamino]pyrimidin-4-yyli}-2-[2-(7 -fluori-3-metyyli-1,2,3,4- tetrahydroisokinolin-2-yyli)-2-oksoetyyli]-2,3-dihydro-1H-isoindol-1-oni 2-(6-15-kloori-2-[(oksan-4-yylijamino]pyrimidin-4-yyli]-1-okso-2,3-dihydro-1H-isoindol- 2-yyli)-N-(1-hydroksi-2-metyylipropan-2-yyli)-N-metyyliasetamidi
—2-(6-45-kloori-2-[(oksan-4-yylijamino]pyrimidin-4-yyli]-1-okso-2,3-dihydro-1H-isoindol- 2-yyli)-N-(1-metyylisyklo propyylijasetamidi 2-(6-15-kloori-2-[(oksan-4-yylijamino]pyrimidin-4-yyli]-1-okso-2,3-dihydro-1H-isoindol- 2-yyli)-N-(1-metyylisyklopentyyli)asetamidi 6-{5-kloori-2-[(oksan-4-yyliyamino]pyrimidin-4-yyli}-2-(2-okso-2-{1H,2H,3H,4H-
pyrrolo[1,2-a]pyratsin-2-yylitetyyli)-2,3-dihydro-1H-isoindol-1-oni 6-{5-kloori-2-[(oksan-4-yyliyamino]pyrimidin-4-yyli}-2-[2-(2,5-dimetyylimorfolin-4-yyli)- 2-oksoetyyli]-2,3-dihydro-1H-isoindol-1-oni 2-(6-15-kloori-2-[(oksan-4-yylijamino]pyrimidin-4-yyli]-1-okso-2,3-dihydro-1H-isoindol- 2-yyli)-N-metyyli-N-(2-metyylibutan-2-yylijasetamidi
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